1. Field of the Invention
The present invention relates generally to the field of pharmaceutics and medicine. More particularly, it concerns pharmaceutical implants for drug delivery and methods of use thereof.
2. Description of Related Art
There have been many therapeutic methods developed to treat brain cancer, including surgery, radiotherapy and chemotherapy. The present invention relates to pharmaceutical compositions that have activity as anti-cancer agents and to the methods for the treatment of cancer in patients.
Glioblastoma Multiforme is a grade 4 astrocytoma. It is an aggressive cancer that grows from the supportive cells in the brain and is diffusely infiltrative. The current standard treatment is aggressive surgical debulking followed by combined modality therapy of chemotherapy and radiation. Despite the neurosurgeon successfully resecting all visible abnormal tissue during surgery, there are normally many cancer cells that extend well past the resection cavity and are still present in the patient after the surgery. The average survival rate for patients with glioblastoma multiforme who have had aggressive treatments, including surgical resection, radiotherapy and chemotherapy, has been reported to be about fourteen months. It has also been reported that less than 30% of patients survive two years. Long-term survival is extremely rare.
Billions of dollars have been spent over the past 30 years on new therapies with survival benefits only increasing on the scale of months, not years, and presently no curative therapies exist. Outside of standard chemotherapeutics, antiangiogenics have shown only minimal benefit. Currently, researchers are working on individualized therapy based on specific genetic mutations of a patient's individual tumor. Vaccines are being developed to combat some of these mutations. Local chemotherapy at the tumor resection site has also been attempted with some minimal degree of success. From a scientific standpoint, trials have shown statistically significant survival improvements, but a survival expectation of 15 months rather than 13 months may represent only a very modest improvement for the patient. Although researchers have successfully cured cancer in some animal models, this success has rarely been duplicated in humans with glioblastoma.
A variety of biodegradable polymers, including the polyesters and polyanhydrides have been reported in the literature as carrier polymers for anti-cancer compounds. Of these materials, polylactide-co-glycolic acid (PLGA) has been extensively studied. However, although various biodegradable polymeric materials have been tested for drug delivery, relatively few commercial products that have reached the marketplace utilize either polyesters or polyanhydrides.
One such product that has been marketed is the Gliadel® wafer implant that contains carmustine for the treatment of malignant gliomas. Gliadel® has been on the market for almost twenty years and is the only FDA approved local implant to treat glioblastoma multiforme. There are presently no generic equivalents on the market. The polyanhydride carrier in the Gliadel® implants is a co-polymer, polifeposan, which consists of 1,3-bis(p-carboxyphenoxy) propane and sebacic acid in a molar ratio of 80 to 20. Molecules of active ingredient are distributed through the polymer matrix, which controls drug delivery at the site of the implant. The product is designed to deliver therapeutic levels of the drug that cannot be achieved with other routes of drug delivery, including i.v. and oral. It has been reported that the median survival of patients with Gliadel® wafers for recurrent glioblastoma was thirty-one weeks compared to twenty-three weeks for those on placebo, although this was not statistically significant. Survival benefit was indeed statistically significant in patients with newly diagnosed glioblastoma, although the benefit is deemed as modest by most (˜2 months).
The increase in side effects such as seizures, wound healing difficulties, the development of cysts, and reactive brain edema seen with the Gliadel® wafers has been a major concern to neurosurgeons wishing to use this product on their patients. Up to eight wafers can be implanted in a patient following removal of the tumor. There have been reports where some neurosurgeons have re-operated to remove these wafers from patients due to severe adverse side effects.
Several theories have been proposed regarding the reasons for increased side effects and toxicity of the Gliadel® wafers in patients when compared to a placebo. For implants based on the biodegradable polyesters and polyanhydrides, there is a potential for toxicity from dose dumping (burst effect), inconsistent drug release and the breakdown of the polymer from hydrolysis or enzymatic degradation. The by-products of polyanhydride polymer degradation include the formation of carboxylic acids amongst other byproducts. The presence of agents to prevent oxidation of the polymer in the solid state may also contribute to these side effects. Irritation at the cellular level by these low molecular weight degradation compounds may be one of the causes of toxic side effects. Slight variations in the molecular weight of the polymer may also result in higher levels of low molecular weight fractions, which will biodegrade faster than the higher molecular weight fractions in the polymeric carrier. Acidic by-products can also be generated during storage of the polymers, which may influence the long term chemical stability of the biologically active compound. Since these polyanhydrides are soluble in most organic solvents, the incorporation of a therapeutic agent into such polymers generally occurs using an organic solvent which dissolves the polymer and often times the anticancer compound, prior to the evaporation of the solvent to form the finished delivery system. These organic solvents used to dissolve the polymers include dichloromethane, acetone, tetrahydrofuran, and ethyl acetate and residual solvents in these polymeric devices have their own inherent toxicity. Dichloromethane is one of the most popular solvents reported in the literature to prepare films or wafers, microparticles, and microcapsules of drug-containing biodegradable polymeric formulations. The FDA has classified dichloromethane as a Class 2 solvent, which should be limited in pharmaceutical products due to its inherent toxicity. In 2012, the limit for this solvent in a pharmaceutical product was six hundred parts per million. The breakdown or erosion of a polyester or a polyanhydride based delivery system at the site of implantation in the brain or at other sites of the body may cause the formation of particles or agglomerate of polymer that can irritate surrounding tissue, which may result in adverse side effects.
Certain problems exist for current treatments for glioblastoma multiforme. The current standard treatment for patients suffering from glioblastoma multiforme is to begin taking oral temozolomide capsules two to four weeks after surgery. Radiation treatments are usually initiated in a similar timeframe. The delay allows for the wound to begin the healing process. The disadvantage of the delay is that cancer cells continue to grow during this time period.
Temozolamide can also display adverse side effects. Commercial capsules of temozolomide are available in doses ranging from 5 mg to 250 mg. The drug has a short biological half-life of approximately 1½ hours and thus must be frequently administered to patients to maintain therapeutic levels. Multiple side effects have been reported for temozolomide including nausea, vomiting, constipation, headache and fatigue. These side effects occur in greater than 30% of patients taking temozolomide capsules. Other, less common, side effects have also been reported. Various compositions have been generated in an attempt to try to alter the release of temozolamide, such as the tableted microspheres described in U.S. Pat. No. 8,821,913.
Lipids have been studied for applications such as intramuscular implants and excipients in parenterals and oral solid dosage forms; however, major problems have been observed with implants and oral tablets that rely upon lipids to retard drug release, include erratic and incomplete drug release performance. “Tailing”, is a phenomenon, where the final 15-25% of the drug remains locked in the wax matrix, resulting in subtherapeutic levels of the drug substance.
Additional efforts to generate delivery systems have also resulted in various challenges. To resolve the erratic release properties and physical stability issues with lipid based systems, numerous researchers have included water soluble pore forming polymers such as polyethylene glycol in the formulation. Hydrophilic polymers have also been studied as retardant carrier excipients in solid dosage forms, including implants. However, the dissolution and swelling properties of these implants would result in high levels of drug being released directly into the brain cavity over a short period of time. For implants that deliver anti-cancer compounds to the cavity of the brain following surgical removal of the tumor, drug release over a period of 1-2 days would be ineffective since therapeutic levels of the drug need to be maintained over periods of weeks, not days. Furthermore, by releasing the drug directly into the fluid of the brain cavity, the concentration would be low resulting in minimal diffusion of the active drug molecules across the surface of the cavity into the brain. In addition, the drug would circulate to other normal portions of the central nervous system, possibly leading to side effects. Clearly, there is a need for improved methods and implants for the treatment of brain tumors.